Therapeutic Use of Immunoglobulins
2010; Elsevier BV; Volume: 57; Issue: 1 Linguagem: Inglês
10.1016/j.yapd.2010.08.005
ISSN1878-1926
AutoresE. Richard Stiehm, Jordan S. Orange, Mark Ballow, Heather K. Lehman,
Tópico(s)Blood groups and transfusion
ResumoAntibodies have been used for more than a century to prevent and treat illness, neutralize drugs and poisons, and accentuate or depress the immune system. Their specificity and diversity and their relative safety make them potent therapy in antibody deficiencies, certain infections and several autoimmune/inflammatory disorders. This article discusses 3 principal uses of immunoglobulins: for infectious diseases, for immunodeficiency, and for immunomodulation. These subjects are discussed in that order, because antibody was first used for infections (since the 1890s), next used for immunodeficiency (since the 1950s), and then used for immunomodulation (since the 1970s, after the introduction of intravenous immunoglobulin [IVIG]). The last use, for a great variety of disorders, is now the largest consumer for immunoglobulin products. This article does not discuss the use of therapeutic monoclonal antibodies, of which 18 are now licensed in the United States, and more are in the pipeline. The therapeutic use of monoclonals for infections and for immunomodulation is in its neonatal period, and, like infants, great expectations have been bestowed upon them. Emil von Behring was awarded the first Nobel Prize in Medicine in 1901 for development of equine antiserum for the treatment of diphtheria and tetanus. His citation stated "For his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and death." Since then antibodies in multiple forms (animal and human serums, immune globulins and monoclonal antibodies) have been developed, primarily for prevention of infectious diseases, and less commonly for their treatment. These antibodies are presented in Table 1. This section reviews their uses, with an emphasis on their value in the treatment of human infections, as summarized in Table 2.Table 1Antibody preparations available for passive immunity in the United StatesProductAbbreviation(s)/brand name(s)Principal useStandard Human Immune Serum Globulins (HISG, γ-Globulin)Immune globulin, intravenousIVIG, IGIVTreatment of antibody deficiency, immune thrombocytopenic purpura, Kawasaki disease, other immunoregulatory and inflammatory diseasesImmune globulin, intramuscularImmunoglobulin, IGIMTreatment of antibody deficiency; prevention of measles, hepatitis AImmune globulin, subcutaneousSCIGTreatment of antibody deficiencySpecial Human Immune Serum Globulins for Intramuscular or Subcutaneous UseHepatitis B immune globulinHBIGPrevention of hepatitis BVaricella-zoster immune globulinVZIGPrevention or modification of chickenpoxRabies immune globulinRIGPrevention of rabiesTetanus immune globulinTIGPrevention or treatment of tetanusVaccinia immune globulinVIGPrevention or treatment of vaccinia, prevention of smallpoxRho(D) immune globulinRhoGAMPrevention of Rh hemolytic diseaseSpecial Human Intravenous Immune GlobulinsCytomegalovirus immune globulinCMV-IVIG, CMVIG, CytoGamPrevention or treatment of cytomegalovirus infectionHepatitis B immune globulin, intravenousHepaGam BPrevention of hepatitis B (including liver transplantation)Vaccinia immune globulin, intravenousVIG-IVIGPrevention or treatment of vaccinia, prevention of smallpoxRho(D) immune globulin intravenousWinRho SDFTreatment of immune thrombocytopenic purpuraBotulinum immune globulinBIG, Baby BIGTreatment of newborn botulismAnimal Serums and GlobulinsTetanus antitoxin (equine)TATPrevention or treatment of tetanus (when TIG unavailable)Diphtheria antitoxin (equine)DATTreatment of diphtheriaBotulinum antitoxins (equine heptavalent)aFab fragment.HBATTreatment of botulismLatrodectus mactans antivenin (equine)Treatment of black widow spider bitesCrotalidae polyvalent antivenin (equine)Treatment of most snake bitesCrotalidae polyvalent immune Fab (ovine)aFab fragment.Treatment of most snake bitesMicrurus fulvius antivenin (equine)Treatment of coral snake bitesDigoxin immune Fab fragments (ovine)aFab fragment.Digibind, DigiFabTreatment of digoxin or digitoxin overdoseLymphocyte/thymocyte immune globulin (equine)Equine ATG, AtgamImmunosuppressionLymphocyte/thymocyte immune globulin (rabbit)Rabbit ATG, thymoglobulinImmunosuppressiona Fab fragment. Open table in a new tab Table 2Summary of the efficacy of antibody in the prevention and treatment of infectious diseasesModified from Stiehm ER, Keller MA. Passive immunization. In: Feigen RD, Cherry JD, Demmler-Harrison GJ, et al, editors. Textbook of pediatric infectious diseases. 6th edition. Philadelphia: Saunders/Elsevier; 2009. p. 3447–79.InfectionProphylaxisTreatmentBacterial InfectionsRespiratory infections (streptococcal, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae)Proved (NR)aRecommended for immunodeficient patients.Proved (NR)DiphtheriaUnproved (NR)ProvedPertussisUnproved (NR)Unproved (NR)TetanusProvedProvedOther clostridial infections Clostridium botulinumProvedProved Newborn botulismUnprovedProved Clostridium difficileUnprovedProbable benefitStaphylococcal infections Toxic shock syndromeUnproved (NR)Probable benefit Antibiotic resistanceUnprovedPossible benefit (NR) Staphylococcus epidermidis in newbornsUnprovedPossible benefitToxic shockUnproved (NR)Probable benefitNewborn sepsisPossible benefit (NR)Probable benefitShock, intensive care, and traumaUnprovedPossible benefit (NR)Pseudomonas infections Cystic fibrosisUnproved (NR)Unproved (NR) BurnsUnproved (NR)Unproved (NR)Viral DiseasesHepatitis AProvedNo benefitHepatitis BProvedNo benefitHepatitis CUnproved (NR)No benefitHIV infectionUnproved (NR)Unproved (NR)RSV infectionProvedUnproved (NR)Herpesvirus infections CMVProvedPossible benefit EBVUnproved (NR)Unproved (NR) HSVUnproved (NR)Unproved (NR) VZVProvedUnproved (NR)ParvovirusPossible benefitProved (NR)Enterovirus infections In newbornsUnprovedPossible benefit EncephalomyelitisPossible benefitProbable benefit (NR)aRecommended for immunodeficient patients. PoliovirusProved (NR)Unproved (NR)EbolaUnprovedUnprovedRabiesProvedNo benefitMeaslesProvedNo benefitRubellaUnproved (NR)No benefitMumpsUnproved (NR)No benefitTick-borne encephalitisPossible benefitNo benefitVacciniaProvedProvedVariolaProvedUnprovedAbbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; NR, not recommended; RSV, respiratory syncytial virus; VZV, varicella-zoster virus.a Recommended for immunodeficient patients. Open table in a new tab Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; NR, not recommended; RSV, respiratory syncytial virus; VZV, varicella-zoster virus. Antibody works by several mechanisms. It can neutralize viruses and bacterial toxins, lyse bacteria with the aid of complement, prevent the spread of microbes to adjacent cells or along nerve roots, coat bacteria for opsonization by phagocytes, block microbial attachment by saturating microbial receptors, and facilitate lysis of infected cells by binding them to cytotoxic cells with an Fc receptor. Antibody is particularly valuable in bacterial diseases associated with toxin production because much of the tissue damage results from action of the toxin; these can be neutralized rapidly by antibody before antibiotics kill the bacterium. Anthrax is a rare but serious infection, predominantly of ruminant animals, caused by an aerobic gram-positive rod [1Lucey D. Anthrax.in: Mandel G. Bennett J.E. Donin R. Principles and practice of infectious diseases. 6th edition. Elsevier/Churchill Livingston, Philadelphia2005: 3618-3624Google Scholar]. Humans are infected through the skin (cutaneous anthrax), by ingestion (gastrointestinal anthrax), or by inhalation of anthrax spores (inhalational anthrax) [1Lucey D. Anthrax.in: Mandel G. Bennett J.E. Donin R. Principles and practice of infectious diseases. 6th edition. Elsevier/Churchill Livingston, Philadelphia2005: 3618-3624Google Scholar]. The last often results from prolonged exposure to animal hides or carcasses or infected soil, and rarely by deliberate spore exposure in the bioterrorism setting. After inhalation the spores are ingested by alveolar macrophages and transported to regional nodes, where the spores germinate and release potent exotoxins. These toxins damage cell membranes, increase capillary permeability, cause pulmonary damage, and lead to shock and cardiovascular collapse. A vaccine is available for individuals at high risk for exposure and for the military. Before the antibiotic era and as early as 1903, anthrax antitoxin (usually equine) was used in therapy [2Gold H. Chester P.A. Studies on anthrax: clinical report of ten human cases.J Lab Clin Med. 1935; 21: 134-152Google Scholar]. An antitoxin is of value in a bioterrorism attack, both before and after exposure. The US Government is collecting plasma from immunized donors to develop a human high-titer IGIV [3Cidrap HHS to buy 20,000 courses of anthrax antitoxin.cidrap.umn.edu/cidrap/content/bt/anthrax/news/jun2006anthrax.htmlGoogle Scholar]. A human monoclonal antibody is being tested in animals and humans [4Migone T. Subramanian M. Zhong J. et al.Raxibacumab or the treatment of inhalational anthrax.N Engl J Med. 2009; 361: 135-144Crossref PubMed Scopus (62) Google Scholar]. Many of the adverse effects of diphtheria result from the action of its potent toxin on the heart, central nervous system, and other organs [5Stiehm E.R. Keller M.A. Passive immunization.in: Feigen R.D. Cherry J.D. Demmler-Harrison G.J. Textbook of pediatric infectious diseases. 6th edition. Saunders/Elsevier, Philadelphia2009: 3447-3479Google Scholar]. Thus the prompt use of antitoxin is indicated, in addition to antibiotics [6American Academy of PediatricsDiphtheria.in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics, Elk Grove Village (IL)2009: 280-283Google Scholar]. The dose used depends on the localization and severity of infection, ranging from 20,000 units for mild infection of short duration to 120,000 units for severe illness with neck edema. The equine antitoxin is given intravenously, so must be preceded by skin testing for hypersensitivity and possible desensitization. The antitoxin is available through the US Centers for Disease Control (CDC). A smaller dose of antitoxin can be used in asymptomatic, exposed, susceptible individuals. Before the availability of diphtheria vaccine, antitoxins were given to health care workers caring for patients with diphtheria [7Faber H.K. McIntosh R. History of the American Pediatric Society 1887–1965. McGraw-Hill, New York1966Google Scholar]. Equine antitoxin for the treatment of tetanus was initiated by von Behring in the 1890s for toxin neutralization. Extensive studies have been carried out to determine the optimal dose of antitoxin and the possible benefit of intrathecal antitoxin, particularly in tetanus neonatorum, a common problem in developing countries [8American Academy of PediatricsTetanus.in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics, Elk Grove Village (IL)2009: 655-660Google Scholar]. Since the 1960s a human tetanus immune globulin (TIG) has been available, but in some areas of the world equine antitoxin is still used. TIG is given to unimmunized or incompletely immunized patients who sustain contaminated or deep puncture wounds [8American Academy of PediatricsTetanus.in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics, Elk Grove Village (IL)2009: 655-660Google Scholar]. The recommended dose of TIG is 250 IU, along with initiation of active immunization. If TIG is unavailable, human IVIG can also be used; it contains variable titers of tetanus antitoxin but a minimal dose of 200–400 mg/kg is suggested for tetanus prophylaxis [8American Academy of PediatricsTetanus.in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics, Elk Grove Village (IL)2009: 655-660Google Scholar, 9Lee D.C. Lederman H.M. Anti-tetanus toxoid antibodies in intravenous gamma globulin: an alternative to tetanus immune globulin.J Infect Dis. 1992; 166: 642-645Crossref PubMed Google Scholar]. Clostridium difficile infection of the gastrointestinal tract is usually associated with antibiotic-associated diarrhea, often with pseudomembranous colitis and sometimes toxic megacolon [10Wilcox M.H. Treatment of Clostridium difficile infection.J Antimicrob Chemother. 1998; 41: 41-46Crossref PubMed Google Scholar] Toxic strains of Clostridium difficile release 2 distinct toxins, both of which have potent cytotoxic and inflammatory properties [11Cleary R. Clostridium difficile-associated diarrhea and colitis: clinical manifestations, diagnosis, and treatment.Dis Colon Rectum. 1998; 41: 1435-1449Crossref PubMed Google Scholar]. Infection generally leads to an antibody response to the toxin, and most individuals older than 2 years have such antibodies. High levels of these antibodies acquired after colonization may result in the asymptomatic carrier state [12Kyne L. Warny M. Qamar A. et al.Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin.N Engl J Med. 2000; 342: 390-397Crossref PubMed Scopus (429) Google Scholar]. Some patients with symptomatic infection, many of whom are immunodeficient or immunosuppressed, develop antibiotic-resistant diarrhea; many have low or absent IgG antibodies to toxin A. Such patients may respond to IVIG given 300 to 500 mg/kg every 1 to 3 weeks [13McPherson S. Rees C.J. Ellis R. et al.Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea.Dis Colon Rectum. 2006; 49: 640-645Crossref PubMed Scopus (128) Google Scholar]. Such therapy increases antitoxin levels, controls the diarrhea, and prevents relapses [14Leung D. Kelly Y.M. Boguniewicz C.P. et al.Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin.J Pediatr. 1991; 118: 633-637Abstract Full Text PDF PubMed Google Scholar, 15Salcedo J. Keates S. Pothoulakis C. et al.Intravenous immunoglobulin therapy for severe Clostridium difficile colitis.Gastroenterology. 1997; 41: 366-370Google Scholar]. Controlled trials have not been performed. Botulism is a severe paralytic poisoning resulting for the ingestion or absorption of neurotoxin or spores of Clostridium botulinum. Several variants are recognized: food poisoning from ingestion of contaminated canned food, wound botulism from a contaminated soft-tissue infection, inhalational botulism among individuals working with the toxin or in a bioterrorist event, infantile botulism (see next section), and adult-type infant botulism in adults with preexisting gastrointestinal disease [16Arnon S.S. Schechter R. 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Kamin S.S. et al.Severe botulism after focal injection of botulinum toxin.Neurology. 2006; 67: 1855-1856Crossref PubMed Scopus (30) Google Scholar]. An heptavalent fab fragment equine antitoxin (HBAT) to types A, B, C, D, E, F and G is available in the United States through the CDC [21Centers for Disease Control and Prevention (CDC) Investigational heptavalent botulinum antitoxin (HBAT) to replace licensed botulinum antitoxin AB and investigational botulinum antitoxin E.MMWR Morb Mortal Wkly Report. 2010; 59: 299PubMed Google Scholar, 22American Academy of PediatricsBotulism and infant botulism.in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics, Elk Grove Village (IL)2009: 259-262Google Scholar]. Sensitivity testing must be conducted before their use. Antitoxin to all 3 types is given unless the toxin type is known. Additional doses may be needed in severe wound botulism. Antitoxin can also by used prophylactically in individuals known to have ingested contaminated food. It is not used for infantile botulism. This severe paralytic disorder of infants results from the ingestion of Clostridium botulinum spores in baby formulae or food, resulting in slow onset of constipation, abdominal bloating, poor feeding, and respiratory paralysis [22American Academy of PediatricsBotulism and infant botulism.in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics, Elk Grove Village (IL)2009: 259-262Google Scholar]. Such infants must be hospitalized for prolonged periods for tube feeding and respiratory support, often for as long as 6 to 9 months. Human IV botulism immune globulin is available for treatment of infantile botulism [23Arnon S.S. Schechter R. Maslanka S.E. et al.Human botulism immune globulin for the treatment of infant botulism.N Engl J Med. 2006; 345: 462-471Crossref Scopus (135) Google Scholar]. Despite its high cost ($50,000 per vial) it is cost-effective because of the shortened hospital stay needed. There is no antitoxin for gas gangrene. Respiratory infections with Streptoccocci, Streptococcus pneumonia, Haemophilus influenzae, and Neisseria meningitides are reduced in immunodeficient patients receiving immunoglobulin therapy. These patients include young infants with poor antibody responses to polysaccharide antigens, patients infected with the human immunodeficiency virus (HIV), and patients with primary antibody immunodeficiencies. Before antibiotics, immune serum or animal serum was used as therapy for severe bacterial infection [24Alexander H.E. Treatment of Haemophilus influenzae infection and of meningococcic and pneumococcic meningitis.Am J Dis Child. 1943; 66: 172-187Google Scholar, 25Casadevall A. Scharff M.D. Return to the past: the case for antibody-based therapies in infectious diseases.Clin Infect Dis. 1995; 21: 150-161Crossref PubMed Google Scholar]. Other studies suggest that a large dose of IVIG decreases the frequency of otitis in patients with recurrent otitis and normal immunity [26Simoes E.A.F. Groothuis J.R. Tristram D.A. et al.Respiratory syncytial virus-enriched globulin for the prevention of acute otitis media in high risk children.J Pediatr. 1996; 129: 214-219Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]. Thus regular use of IVIG in antibody-deficient patients in doses of 400 to 600 mg/kg every 3 to 4 weeks or an equivalent amount given subcutaneously decreases the frequency and severity of otitis and other respiratory tract infections [27Mofenson L.M. Moye Jr., J. Bethel J. et al.Prophylactic intravenous immunoglobulin in HIV-infected children with CD4+ counts of 0.20 × 109/L or more: effect on viral, opportunistic, and bacterial infections.JAMA. 1992; 268: 483-488Crossref PubMed Google Scholar, 28National Institute of Child Health and Human Development (NICHHD) Intravenous Immunoglobulin Study GroupIntravenous immune globulin for the prevention of bacterial infections in children with symptomatic human immunodeficiency virus infection.N Engl J Med. 1991; 325: 73-80Crossref PubMed Google Scholar]. Circulating antibody may play a role in the prevention and treatment of invasive group A streptococcal infection [29Casadevall A. Passive antibody therapies: progress and continuing challenges.Clin Immunol. 1999; 93: 5-15Crossref PubMed Scopus (51) Google Scholar]. Newborns with transplacental antibody and patients on IVIG rarely develop streptococcal illnesses. Equine antitoxin was used with some success in the treatment of erysipelas and scarlet fever in the 1920s and 1930s [30Lucchesi P.F. Bowman J.E. Antitoxin versus no antitoxin in scarlet fever.JAMA. 1930; 103: 1049-1051Crossref Google Scholar]. A preventive vaccine against the streptococcal M protein has been contemplated but is not yet unavailable. Treatment with IVIG, in addition to antibiotics, is probably beneficial [25Casadevall A. Scharff M.D. Return to the past: the case for antibody-based therapies in infectious diseases.Clin Infect Dis. 1995; 21: 150-161Crossref PubMed Google Scholar, 31Perez C.M. Kubak B.M. Cryer H.G. et al.Adjunctive treatment of streptococcal toxic shock syndrome using intravenous immunoglobulin: case report and review.Am J Med. 1997; 102: 111-113Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar]. Streptococcal pyrogenic exotoxins types A, B, and C and mitogenic factor elaborated by certain strains of streptococci may be responsible for these complications. These exotoxins are potent superantigens that activate certain T lymphocytes directly, leading to synthesis and/or release of multiple cytokines with resultant shock, fever, and organ failure. IVIG contains neutralizing antibodies to these antigens of varying titers from batch to batch [32Schrage B. Duan G. Yang L.P. et al.Different preparations of intravenous immunoglobulin vary in their efficacy to neutralize streptococcal superantigens: implications for treatment of streptococcal toxic shock syndrome.Clin Infect Dis. 2006; 43: 743-746Crossref PubMed Scopus (27) Google Scholar]. Despite this variability IVIG is recommended, in addition to antibiotics, in the management of these infections, not only to neutralize pyrogenic toxins but to dampen cytokine storm and release [33Lamothe F. D'Amico P. Ghosen P. et al.Clinical usefulness of intravenous human immunoglobulins in invasive group A streptococcal infections: case report and review.Clin Infect Dis. 1995; 21: 1469-1470Crossref PubMed Google Scholar]. Controlled trials are unavailable but case reports and large series compared with historical controls are encouraging [34Kaul R. McGeer A. Norrby-Tegllund A. et al.Intravenous immunoglobulin for streptococcal toxic shock syndrome–a comparative observational study.Clin Infect Dis. 1999; 28: 800-807Crossref PubMed Google Scholar]. Large doses of IVIG are recommended (eg, 1–2 g/kg over several days). Staphylococcal infections are ubiquitous and of varying severity, ranging from superficial skin infections to deep-seated cellulitis, osteomyelitis, and overwhelming shock [35American Academy of PediatricsStaphylococcal infections.in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics, Elk Grove Village (IL)2009: 601-615Google Scholar, 36Melish M.E. Murata S. Fukunaga C. et al.Vaginal tampon model for toxic shock syndrome.Rev Infect Dis. 1989; 11 (238–46): 219-228Crossref Google Scholar]. These severe infections occur when the organism is resistant to antibiotics or is a strain associated with toxin production. One well-recognized syndrome is toxic shock associated with tampon use in menstruating women [36Melish M.E. Murata S. Fukunaga C. et al.Vaginal tampon model for toxic shock syndrome.Rev Infect Dis. 1989; 11 (238–46): 219-228Crossref Google Scholar]. This syndrome results from release of the toxic shock syndrome toxin-1, a potent superantigen that initiates the release of multiple cytokines and a clinical picture of rapidly progressive fever, shock, and organ failure. Most authorities recommend a high dose of IVIG to neutralize the toxin and dampen cytokine storm [35American Academy of PediatricsStaphylococcal infections.in: Pickering L.K. Baker C.J. Kimberlin D.W. Red Book: 2009 Report of the Committee on infectious diseases. 28th edition. American Academy of Pediatrics, Elk Grove Village (IL)2009: 601-615Google Scholar, 37Suen J. Chesney P.J. Davis J.P. Toxic shock syndrome.in: Feigen R.D. Cherry J.D. Demmler-Harrison G.J. Textbook of pediatric infectious diseases. 6th edition. Saunders/Elsevier, Philadelphia2009: 862-884Google Scholar]. A second situation in which IVIG may be of value is in neonatal staphylococcal infection, usually coagulase-negative Staphylococcus epidermidis. This is the most common cause of sepsis in premature infants and is aggravated in part by the use of catheters and central lines [38Fischer G.W. Cieslak T.J. Wilson S.R. et al.Opsonic antibodies to Staphylococcus epidermidis: in vitro and in vivo studies using human intravenous immune globulin.J Infect Dis. 1994; 169: 324-329Crossref PubMed Google Scholar, 39Jenson H.B. Pollock B.H. The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis.Semin Perinatol. 1998; 22: 50-63Abstract Full Text PDF PubMed Scopus (34) Google Scholar]. One controlled study indicated that IVIG was of value in decreasing the incidence of this infection [40Baker C.J. Melish M.E. Hall R.T. Intravenous immune globulin for the prevention of nosocomial infection in low-birth-weight neonates.N Engl J Med. 1992; 327: 213-219Crossref PubMed Google Scholar]. Other studies were not confirmatory, possibly because of differences in titer for the protective antibodies [39Jenson H.B. Pollock B.H. The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis.Semin Perinatol. 1998; 22: 50-63Abstract Full Text PDF PubMed Scopus (34) Google Scholar]. Immunoglobulin is also used in the treatment of antibiotic-resistant staphylococcal infection. Older studies from Waisbren [41Waisbren B.A. The treatment of bacterial infections with the combination of antibiotics and gamma globulin.Antibiot Chemother. 1957; 7: 322-332Google Scholar] and current studies from Russia suggest clinical benefit [42Kelly J. Immunotherapy against antibiotic-resistant bacteria: the Russian experience with an antistaphyloccocal hyperimmune plasma and immunoglobulin.Microbes Infect. 2000; 2: 1383-1392Crossref PubMed Scopus (13) Google Scholar]. Animal studies support such a combined approach [43Fisher M.W. Synergism between human gamma globulin and chloramphenicol in the treatment of experimental bacterial infections.Antibiot Chemother. 1956; 7: 315-321Google Scholar]. Newborns, particularly premature newborns with birth weight less than 2000 g are potential candidates for immunoglobulin therapy in view of the frequency and severity of infections. All newborns have low levels of IgM and IgA, and, if premature, a deficiency of transplacental maternal IgG, the deficiency of which is proportional to the degree of immaturity [44Lewis D.B. Tu W. The physiologic immunodeficiency of immaturity.in: Stiehm E.R. Ochs H.D. Winkelstein J.W. Immunologic disorders in infants and children. 5th edition. Elsevier/Saunders, Philadelphia2004: 687-760Google Scholar]. Premature infants also have defects in antibody synthesis, complement levels, opsonic activity, neutrophil mobilization and killing, and cellular immune responses [44Lewis D.B. Tu W. The physiologic immunodeficiency of immaturity.in: Stiehm E.R. Ochs H.D. Winkelstein J.W. Immunologic disorders in infants and children. 5th edition. Elsevier/Saunders, Philadelphia2004: 687-760Google Scholar]. Accordingly several studies sought to determine the value of IGIV in the prevention or early treatment of infection in premature infants. These studies differ in terms of entry criteria, immunoglobulin dose and duration, and end points (eg, type and severity of infection, survival). Meta-analyses of prospective, randomized, placebo-controlled prevention studies suggest a slight reduction (3%) in the frequency of sepsis but no difference in mortality, length of nursery stay, or other complications of prematurity [45Jenson H.B. Pollock B.H. Meta-analyses of the effectiveness of intravenous immune globulin for prevention and treatment of neonatal sepsis.Pediatrics. 1997; 99: E2Crossref PubMed Google Scholar, 46Lacy J.B. Ohlsson A. Administration of intravenous immunoglobulins for prophylaxis or treatment of infection in preterm infants: meta-analysis.Arch Dis Child. 1995; 72: F151-F155Crossref Google Scholar, 47Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low birth-weight infants (Cochrane Review). The Cochrane Library. Oxford. Issue 1. 2001.Google Scholar]. By contrast meta-analysis of 6 controlled studies for the treatment of proven sepsis, involving 262 premature infants, showed that IGIV therapy reduced mortality from 20% to 11%, a significant difference [48Ohlsson A. Lacy J.B. Intravenous immunoglobulin for suspected or subsequently proven infection in neonates.Cochrane Database Syst Rev. 2004; (CD001239)Google Scholar]. There was a suggestive benefit for infants with suspected sepsis also. Infants with neutropenia may particularly benefit. Because a common cause of neonatal sepsis is Staphylococcus epider
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